Optimized Systemic Dosing with CpG DNA Enhances Dendritic Cell-Mediated Rejection of a Poorly Immunogenic Mammary Tumor in BALB/c Mice
Optimized Systemic Dosing with CpG DNA Enhances Dendritic Cell-Mediated Rejection of a Poorly Immunogenic Mammary Tumor in BALB/c Mice
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DOI：
10.1111/j.1752-8062.2008.00073.x
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发表时间：
2009-02-01
影响因子：
3.9
通讯作者：
Baar, Joseph
中科院分区：
文献类型：
--
作者：
Cai, Quan;Kublo, Lyubov;Baar, Joseph
为了模拟树突状细胞（DC）治疗免疫原性差的乳腺肿瘤的临床试验，我们用裂解物脉冲的DC和CpG DNA治疗了已建立TS/A乳腺肿瘤的BALB/c小鼠。我们观察到体外激活DC所需的CpG DNA剂量不足以介导体内肿瘤排斥。因此，我们进行了体内研究，以确定用于肿瘤治疗的CpG DNA的最佳剂量，定义为介导完全肿瘤排斥的最低和最不频繁施用的CpG DNA剂量。我们表明，一个引发剂量的15纳摩尔和一个加强剂量的10纳摩尔的CpG DNA给予间隔7天，分别与裂解物负载的DC足以介导体内完全的肿瘤排斥。该剂量的CpG DNA比体外激活DC所需的剂量高42倍，但与小鼠中的任何毒性无关。此外，治愈的小鼠拒绝了随后用新鲜TS/A肿瘤进行的攻击，并且肿瘤排斥需要CD 4（+）和CD 8（+）T细胞。我们的结论是，有效的DC为基础的治疗免疫原性差的TS/A肿瘤增强优化剂量的CpG DNA。我们的数据对基于DC的乳腺癌免疫治疗临床试验具有重要意义。
To model a clinical trial of dendritic cell (DC) therapy of a poorly immunogenic mammary tumor, we treated BALB/c mice bearing an established TS/A mammary tumor with lysate-pulsed DCs and CpG DNA. We observed that the dose of CpG DNA required to activate DCs in vitro was insufficient to mediate tumor rejection in vivo. We therefore undertook in vivo studies to identify an optimized dose of CpG DNA for tumor therapy, defined as the lowest and least frequently administered dose of CpG DNA that mediated complete tumor rejection. We show that one priming dose of 15 nanomoles and one booster dose of 10 nanomoles of CpG DNA given 7 days apart, respectively, with lysate-loaded DCs were sufficient to mediate complete tumor rejection in vivo. This dose of CpG DNA was 42-fold higher than that required to activate DCs in vitro but was not associated with any toxicity in mice. Also, the cured mice rejected a subsequent challenge with fresh TS/A tumor, and both CD4(+) and CD8(+) T cells were required for tumor rejection. We conclude that effective DC-based therapy of a poorly immunogenic TS/A tumor is enhanced by optimized dosing of CpG DNA. Our data have important implications for DC-based clinical trials of breast cancer immunotherapy.